Thymidylate synthase (TS) is an essential enzyme for DNA synthesis and repair [1] that is expressed at low levels in normal tissues. TS has been reported to be aberrantly overexpressed in a wide range of human cancers including colon, lung, pancreatic, breast, ovarian, neuroendocrine tumors, glioblastoma, lymphoma and sarcoma, and many other tumor types [2-7]. Activated expression of TS plays a direct role in promoting tumorigenesis and results in more aggressive disease [8, 9]. Multiple clinical studies have also confirmed that TS overexpression significantly correlates with the disease stage [10]. TS is a validated therapeutic target for chemotherapy agents, such as 5-fluorouracil, and pemetrexed [11]. These agents are effective in prolonging the survival of patients with colorectal, breast and lung cancer [12-15]. Despite many successes in targeting TS with chemotherapy agents, the ability of fluoropyrimidine TS inhibitors to achieve durable complete remissions is rare in patients with metastatic disease due to induction of TS overexpression [16] and development of resistance that ultimately limits clinical effectiveness [17-20].
The current invention provides novel compounds and derivatives thereof capable of specifically inhibiting TS in vitro and in human cancer cell lines in vivo. The current invention also provides the search strategy related to the discovery of these novel TS inhibitors. The newly discovered small molecule TS inhibitors of the current invention can have profound implications for the treatment and prevention of a broad range of tumors since TS is a target for aberrant overexpression in many human cancer subtypes, including those that were not sensitive to currently used therapies.